Transition metal-catalyzed cross-coupling reactions are useful in a wide range of chemical transformations that have application in pharmaceuticals and materials chemistry. The transition metal catalyst plays a key role in the catalytic cycle. For example, transition metals such as Pd may be ligated with suitable spectator ligands that stabilize the metal center and impart the reactivity patterns required for catalytic performance. Tertiary phosphines are among the most widely used precatalyst ligands for cross-coupling reactions. One of the most widely-used Pd-phosphine catalyst systems today is based on triphenylphosphine (PPh3). However, such catalyst systems often display moderate reactivity and substrate scope. In some cases, the catalyst or precatalyst system, such as [Pd(PPh3)4], exhibits a short shelf life and readily decomposes upon storage. Other phosphine ligands have been developed, but many require multi-step syntheses and, thus, are often high in cost. Moreover, a number of phosphines are toxic, air-sensitive and even pyrophoric.
As an alternative to phosphine ligands, N-heterocyclic carbenes (NHCs) have been shown to impart greater stability and increased catalytic activity in transition metal-mediated homogeneous catalysis, relative to phosphines. NHCs have stronger sigma-donating properties relative to phosphine ligands, resulting in stronger bonds formed with the transition metal center. NHC ligands based on 1,3-diarylimidazol-2-ylidenes and their 4,5-dihydro analogs are often used with a Pd metal center. NHCs are typically highly air-sensitive and moisture-sensitive, and metal complexes comprising NHCs are often prepared in situ by deprotonation of the corresponding (4,5-dihyrdo)imidazolium salts. For example, some catalytic systems may involve the separate addition of various components of the catalytically active species (e.g., metal source, salts of carbene ligands, etc.) for the in situ formation of the catalytically active species. However, while such catalyst systems have been shown to be useful, in many cases it may be difficult to control the amount and/or chemical composition of the catalytically active species formed.
Accordingly, improved methods are needed.